CD180 and the Macrophage Response to Legionella neumophila Legionella pneumophila (Lp) is a gram-negative intracellular bacterium that infects human alveolar macrophages and causes a pneumonic illness known as Legionnaire's Disease (LD). The role of CD180 (RP105), a non-signaling member of the TLR family that regulates TLR2 and TLR4 function, in Legionella pathogenesis is unknown. We hypothesized that CD180 regulates susceptibility to Lp infection in mice and humans. We infected bone-marrow derived macrophages with Lp and observed significantly greater replication in CD180-/- mice compared to C57BL/6 controls over a range of MOIs in both wildtype and flagellin-deficient Lp strains. The enhanced replication of Lp in CD180-/- macrophages was not associated with release of key innate immune cytokines, such as IL-1, IL-6, or TNF. Using a case-control study of individuals from a 1999 outbreak of Legionnaire's Disease in the Netherlands, we found CD180 single nucleotide polymorphisms that were significantly associated with protection from LD (OD 0.27-0.50). One of these polymorphisms was associated with decreased expression of CD180 in monocytes. In this application, we propose to examine the in vitro mechanisms underlying CD180-dependent host resistance to Lp infection in mice. In addition, we will examine human variants of CD180 and their role in regulating monocyte and macrophage responses to Lp infection. We will examine whether alteration of CD180 function, via polymorphisms in humans or targeted gene deletion in mice, changes the host response to a flagellated, intracellular bacteria at the molecular and cellular level. Individuals with CD180 deficiency provide a unique opportunity to study the in vitro and in vivo effects of human CD180 variation and, along with CD180-/- mice, will enable us to examine the role of CD180 in the innate immune response to Lp. The immunogenetic models derived from these studies will illuminate mechanisms of host susceptibility to diseases caused by Lp and possibly other intracellular bacteria and culminate in novel insights for future therapies.